Mechanotransduction in Mammary Epithelial Cells and Breast Cancer Risk

Abstract

Breast cancer is a leading cause of female morbidity and mortality, contributing to the death of over 500,000 women worldwide each year. Current therapeutic strategies aim to treat the disease after it has developed. However, these treatments often have unpleasant side effects and cancers can become resistant and form metastases. An alternative approach may be improving preventative therapies. To do this, we must first understand the mechanisms linking risk factors to breast cancer development. High mammographic density is a very potent risk factor for breast cancer development, however the mechanisms involved are very poorly understood. High mammographic density is associated with an increased proportion of connective and glandular tissue relative to adipose tissue. Previous work has demonstrated that high-density tissue is mechanically stiffer than low-density. Within this thesis, I show that a stiff environment induces a cancer-like phenotype in mammary epithelial cells including: loss of polarity, disrupted differentiation, increased proliferation, more replicative stress, DNA damage accumulation and colony formation in soft agar. I also suggest a link between this phenotype observed in the stiff environment and both the Yap and RhoA pathways. I also identify a role for epigenetic modifications and the stiff-induced phenotype. Chronic inhibition of histone deacetylase and demethylase enzymes prevent the stiff phenotype from developing and reduce DNA damage accumulation. With additional research, these pathways could be exploited as future prophylactic strategies to treat women with high mammographic density

Date of Award	31 Dec 2017
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andrew Gilmore (Supervisor), Keith Brennan (Supervisor) & Michael White (Supervisor)